Document Detail

A46, a benzothiophene-derived compound, suppresses Jak2-mediated pathologic cell growth.
MedLine Citation:
PMID:  22019628     Owner:  NLM     Status:  MEDLINE    
Hyperkinetic Jak2 tyrosine kinase signaling has been implicated in several hematological disorders, including myeloproliferative neoplasms. Effective Jak2 inhibitors can have significant therapeutic potential. Here, using structure-based virtual screening, we identified a benzothiophene-derived Jak2 inhibitor named A46. We hypothesized that this compound would inhibit Jak2-V617F-mediated pathologic cell growth. To test this, A46 was analyzed for its ability to inhibit recombinant Jak2 protein catalysis; suppress Jak2-mediated pathogenic cell growth in vitro; inhibit the aberrant ex vivo growth of Jak2-V617F-expressing primary human bone marrow cells; and inhibit Jak2-mediated pathogenesis in vivo. To this end, we found that A46 selectively inhibited Jak2-V617F protein when compared to wild-type Jak2 protein. The drug also selectively inhibited the proliferation of Jak2-V617F-expressing cells in both a time- and dose-dependent manner, and this correlated with decreased Jak2 and signal transducers and activators of transcription 5 phosphorylation within treated cells. The Jak2-V617F cell growth inhibition correlated with an induction of cell cycle arrest and promotion of apoptosis. A46 also inhibited the pathologic growth of primary Jak2-V617F-expressing bone marrow cells ex vivo. Lastly, using a mouse model of Jak2-V617F-mediated myeloproliferative neoplasia. A46 significantly reduced the splenomegaly and megakaryocytic hyperplasia in the spleens of treated mice and the levels of interleukin-6 in the plasma. Collectively, our data demonstrate that the benzothiophene-based compound, A46, suppresses Jak2-mediated pathogenesis, thereby making it a potential candidate drug against Jak2-mediated disorders.
Anurima Majumder; Andrew T Magis; Sung O Park; Nicholas C Figueroa; Rebekah Baskin; Annet Kirabo; Robert W Allan; Zhizhuang Joe Zhao; Kirpal S Bisht; György M Keseru; Peter P Sayeski
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-10-20
Journal Detail:
Title:  Experimental hematology     Volume:  40     ISSN:  1873-2399     ISO Abbreviation:  Exp. Hematol.     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2011-12-13     Completed Date:  2012-02-01     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  0402313     Medline TA:  Exp Hematol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  22-34     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.
Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32610, USA.
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MeSH Terms
Apoptosis / drug effects
Bone Marrow Cells / cytology*,  drug effects*,  pathology
Cell Cycle / drug effects
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Janus Kinase 2 / antagonists & inhibitors*,  metabolism
Mice, Transgenic
Structure-Activity Relationship
Thiophenes / chemistry,  pharmacology*
Tumor Cells, Cultured
Grant Support
Reg. No./Substance:
0/1-benzothiophen-2-yl-(4-dimethylaminophenyl)methanol; 0/Thiophenes; EC protein, human; EC Kinase 2

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